Although in the last ten years there have been significant inroads into the molecular, cellular and systems[unreadable] mechanisms that mediate the early stages of contextual fear conditioning, a model of emotional memory,[unreadable] later stages of this process remain poorly understood. Recently our laboratory reported genetic, imaging[unreadable] and reversible lesion evidence that supports the idea that long-term memory for contextual conditioning[unreadable] depends on cortical regions, such as the anterior cingulate. Now, we propose to use a combination of[unreadable] genetics, transgenics, electrophysiology and 2-photon in vivo imaging to unravel the molecular and cellular[unreadable] mechanisms of cortical plasticity that underlie remote emotional memory. The specific aims of Project 1 are:[unreadable] 1- To identify genes specifically required for remote memory for contextual conditioning. In our Reverse[unreadable] Forward Genetic (RFG) pilot screen, out of 55 transgenics and KOs selected with a random number[unreadable] generator from the Jackson Laboratory collection, we found that 2 affect specifically 7-day memory (remote)[unreadable] for contextual conditioning, without disrupting 1-day memory (recent), general activity levels or shock[unreadable] reactivity. We now propose to extend this screen and test contextual fear conditioning in another 350[unreadable] transgenic and KO mutants. These mutants will then be screened for somatosensory (Project 2) and visual[unreadable] (Project 3) plasticity deficits, as a preamble for mechanistic studies (see below) to unravel the molecular and[unreadable] physiological mechanisms underlying the later stages of cortical and behavioral plasticity.[unreadable] 2- To derive region and temporally specific mutations for genes that affect long-term memory for contextual[unreadable] conditioning. We propose to use the loxP/Cre recombinase system to control the cell types, brain regions[unreadable] and temporal expression of the mutations isolated in aim 1. The resulting mice will be tested for memory[unreadable] deficits and will also be studied in Projects 2 and 3.[unreadable] 3- To uncover cortical molecular mechanisms underlying the turnover and stability of spines in the anterior[unreadable] cingulate. Plasticity, including behavioral plasticity (i.e. remote memory), is thought to involve changes in[unreadable] neuronal structure required for consolidation and stability of stored information. We propose to use 2-photon[unreadable] scanning confocal in vivo imaging to examine whether mutations that affect remote memory also affect[unreadable] turnover and stability of spines in cortical regions required for remote memory (i.e. anterior cingulate) in[unreadable] trained and untrained (contextual conditioning) mutants and controls. These studies will parallel related[unreadable] imaging studies carried out in Projects 2 and 3.[unreadable] All together, the studies described here and related studies in Projects 2 and 3 will unravel fundamental[unreadable] molecular, cellular and structural mechanisms of how the neocortex encodes and stores information. These[unreadable] findings will have a key impact on how we study and treat disorders associated with emotional memory.